The overall goal of our laboratory is to enhance the number of head and neck cancer patients that respond to anti-cancer immunotherapy. Recently published clinical trials consistently demonstrate a 15-20% response rate to programmed death receptor-1 (PD-1) checkpoint blocking antibodies in patients with recurrent/metastatic head and neck cancer. Durable responses and immune correlative analyses from these trials are consistent with the activation of anti-tumor immunity. We aim to enhance these responses through combination treatment, and explore different combinations of checkpoint blocking antibodies with standard-of-care, targeted and other immunotherapies. One of the major barriers to effective immunotherapy seems to be the presence of immunosuppressive immune cells alongside the anti-tumor immune cells within the tumor. In head and neck cancers, immature myeloid cells and regulatory T-cells are potent suppressors of anti-tumor immunity. Previously our laboratory had fully characterized different models of oral cavity cancer that model human head and neck cancer that have evidence of an activated anti-tumor immune response (T-cell inflamed tumors) and those that do not (non-T-cell inflamed tumors). These models allow our team to explore treatments designed to enhance an existing anti-tumor immune response, as well as treatment designed to activate an anti-tumor immune response that does not already exist. Our laboratory, along with others, has identified the mechanisms by which tumor infiltrating myeloid cells suppress the function of effector immune cells. Suppression of effector immune cells prevents them from killing cancer cells. Several projects in our laboratory have focused on how to limit recruitment of these immunosuppressive myeloid cells into the tumor microenvironment, and how this limitation enhances anti-tumor responses to both immune checkpoint inhibitors and adoptive cell transfer immunotherapies. One specific project involves the use of a small molecule chemokine inhibitor that blocks the signaling that recruits immature myeloid cells into the tumor microenvironment. Another major focus of our laboratory is how to combine local (not systemic) anti-cancer treatments with immunotherapy to induce a systemic anti-tumor immune response. We have completed several projects using standard ionizing radiation (IR), and shown that when used in specific ways, IR can activate local anti-tumor immune response against tumor antigens. The addition of immune checkpoint inhibitors appears to enhance this anti-tumor response and lead to immune responses against tumors that have not been treated with IR. In a related project, we performed similar experiments but with a novel tumor cell targeting phototherapy activated by near infrared light that was developed at the NIH. We demonstrated that these types of tumor targeting therapies may be able to effectively kill tumor cells and activate anti-tumor immunity while minimizing unwanted side effects to nearby tissues. One other important project in our laboratory this year has been the use of checkpoint inhibitors combined with targeted, small molecule inhibitors that make tumor cells more sensitive to effector immune cell killing. Preliminary work for our laboratory suggests that when T-lymphocytes begin to try to kill a target tumor cell, that the tumor cells pauses its cell cycle, possible to allow recovery from the injury. A new drug blocks a kinase that helps the tumor cell pause its cell cycle, and when tumor cells are exposed to this new drug, they become much more sensitive to T-lymphocyte-induced killing. Furthermore, tumor cells seem to become more sensitive to multiple mechanisms of T-lymphocyte killing, including fast, one-on-one killing of highly sensitive tumor cells and slower, so called bystander killing of more resistant cells. We are working aggressively in our laboratory to begin early phase clinical trials combining these types of small molecule inhibitor treatments with immune checkpoint blockade for patients with advanced head and neck cancer. We are excited to continue our work investigating different combinations of standard-of-care, targeted and immune treatments with checkpoint inhibition, with the ultimate goal of moving each promising combination into early phase clinical trials at the NIH and other academic medical centers.